EP0025108B1 - Maytansinoide, ihre Herstellung und sie enthaltende therapeutischen Zusammensetzungen - Google Patents
Maytansinoide, ihre Herstellung und sie enthaltende therapeutischen Zusammensetzungen Download PDFInfo
- Publication number
- EP0025108B1 EP0025108B1 EP80104462A EP80104462A EP0025108B1 EP 0025108 B1 EP0025108 B1 EP 0025108B1 EP 80104462 A EP80104462 A EP 80104462A EP 80104462 A EP80104462 A EP 80104462A EP 0025108 B1 EP0025108 B1 EP 0025108B1
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- European Patent Office
- Prior art keywords
- alkyl
- compound
- compound according
- phenyl
- isobutyrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- 0 C*C(CC(NC(C(*)=C(C1)O)=CC1CC(C)=CC=CC(C(C1)O)OC)=O)C(C)(*2)C2C(C)C1OC(N)=O Chemical compound C*C(CC(NC(C(*)=C(C1)O)=CC1CC(C)=CC=CC(C(C1)O)OC)=O)C(C)(*2)C2C(C)C1OC(N)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/04—Actinomyces
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/07—Bacillus
- C12R2001/11—Bacillus megaterium
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/465—Streptomyces
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/465—Streptomyces
- C12R2001/585—Streptomyces platensis
Definitions
- This invention relates to novel maytansinoid compounds which are of value as medicines, and to their production and use.
- this invention relates to maytansinoid compounds of the formula: wherein X is H or Cl, R 1 is an alkyl group of 2 to 4 carbon atoms and R 2 is an alkyl group of 1 to 4 carbon atoms or an unsubstituted or a substituted phenyl or aralkyl group and their production and use.
- the C 2-4 alkyl group R 1 is exemplified by ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, etc. Especially preferred is isopropyl.
- the alkyl group R 2 of 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl.
- the aralkyl group R 2 includes, for example, phenyl-C 1-3 alkyl groups (e.g. benzyl, phenethyl, a-methylbenzyl).
- the said phenyl and aralkyl groups R 2 may be substituted.
- the substituents include, for example, C 1-4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), C 1-4 alkoxy groups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy), nitro, amino, mono- or di-C 1-4 alkylamino (e.g. methylamino, ethylamino, dimethylamino, diethylamino), mono- or di-C 1-4 alkanoylamino (e.g.
- halogenated mono- or di-C 1-4 alkanoylamino e.g. trifluoroacetylamino, chloroacetylamino, dichloroacetylamino
- halogens e.g. fluorine, chlorine, bromine, iodine
- halogenated C 1-4 alkyl e.g. trifluoromethyl
- a preferred embodiment provides maytansinoid compounds of formula (I) wherein X is H or Cl, R 1 is C 2-4 alkyl and R 2 is C 1-4 alkyl, phenyl or phenyl-C 1-3 alkyl, said phenyl or phenyl-C 1-3 alkyl being unsubstituted or substituted by C 1-4 alkyl, C 1-4 alkoxy, nitro, amino, mono- or di-C 1-4 alkylamino, mono- or di-C 1-4 alkanoylamino, halogenated mono- or di-C 1-4 alkanoylamino, halogen or halogenated C 1-4 alkyl.
- R 2 SO 2 - preferred species will be shown below as the group of R 2 SO 2 -.
- they include methanesulfonyl, ethanesulfonyl, 2-propanesulfonyl, 2-butanesulfonyl, butanesulfonyl, a-toluenesulfonyl (benzylsulfonyl), ⁇ -ethylbenzenesulfonyl, a-phenylpropanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, o-, m- or p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, p-acetamidobenzenesulfonyl, p-trifluoroacetamidobenzenesulfonyl,
- the compound of formula (1) can be produced for example by reacting a 20-demethoxy-20-hydroxymaytansinol 3-lower carboxylate of the formula: wherein X and R 1 are as previously defined, with a sulfonic acid of the formula: wherein R 2 is as previously defined, or a reactive derivative thereof (e.g. halide, azolide, acid anhydride, etc.).
- the reaction is normally carried out in the presence of a base.
- the base is exemplified by alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), tertiary amines (e.g. triethylamine, pyridine, ⁇ -, ⁇ - or y-picoline, 2,6- lutidine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, dimethylaniline, diethylaniline), imidazole, 2-methylimidazole, triazole, etc.
- alkali metal hydroxides e.g. sodium hydroxide, potassium hydroxide
- alkali metal carbonates e.g. sodium carbonate, potassium carbonate
- tertiary amines e.g. triethylamine, pyridine, ⁇ -, ⁇ - or y-picoline, 2,6- lutidine,
- Such a base is normally used in a proportion of 1 to 20 molar equivalents based on the starting compound (II) and when a tertiary amine which is liquid at room temperature is employed as the base (e.g. triethylamine, pyridine), it may be used also as the reaction solvent.
- a tertiary amine which is liquid at room temperature e.g. triethylamine, pyridine
- the reaction is preferably carried out in a solvent.
- the solvent includes, in addition to the above- mentioned tertiary amine, such solvents as esters (e.g. ethyl acetate), ethers (e.g. diethyl ether, dioxane, tetrahydrofuran), halogenated hydrocarbons (e.g. dichloromethane, chloroform), nitriles (e.g. acetonitrile, propionitrile), aromatic hydrocarbons (e.g. benzene, toluene), dimethylformamide, dimethyl sulfoxide, sulfolane, etc. or a suitable mixture of such solvents.
- esters e.g. ethyl acetate
- ethers e.g. diethyl ether, dioxane, tetrahydrofuran
- halogenated hydrocarbons e.g. dichloromethane, chloroform
- the reaction is preferably conducted in a two phase system of aqueous and organic phases by a procedure which is known as the Schotten-Bauman reaction and in such cases it is sometimes more desirable to conduct the reaction in the presence of a phase transfer catalyst (e.g. tetraethylammonium hydroxide, benzyltrimethylammonium bromide, benzyltriethylammonium iodide, cetyltrimethylammonium chloride or bromide).
- a phase transfer catalyst e.g. tetraethylammonium hydroxide, benzyltrimethylammonium bromide, benzyltriethylammonium iodide, cetyltrimethylammonium chloride or bromide.
- the preferred organic solvent as the organic phase for the reaction is exemplified by halogenated hydrocarbons, aromatic hydrocarbons, etc., while an aqueous solution of alkali metal hydroxide is preferably used as
- the amount of said reactive derivative of sulfonic acid (III) as said sulfonating agent is about 1 to 20 molar equivalents, preferably about 3 to 15 equivalents based on the starting compound (II).
- said reactive derivative is formed in situ, i.e. by the reaction of sulfonic acid (III) with an inorganic halogenating agent (e.g. thionyl chloride), a carbodiimide (e.g. N,N'- dicyclohexylcarbodiimide, N-cyclohexyl-N'-(2-morpholino)ethylhexylcarbodiimide), carbonyldiimidazole or the like within the reaction medium or in the same vessel.
- an inorganic halogenating agent e.g. thionyl chloride
- a carbodiimide e.g. N,N'- dicyclohexylcarbodiimide, N-cyclohexyl-N'-(2-morpholino)ethylhexylcarbodiimide
- carbonyldiimidazole or the like within the reaction medium or in the same vessel.
- the desired product is a compound having, in the moiety which comes of the sulfonylating agent, a group (e.g. OH, NH 2 ) liable to be sulfonylated
- a group e.g. OH, NH 2
- the protective groups which can be utilized include, for example, lower (C 1-4 ) alkanoyl, (e.g. formyl, acetyl), lower (C 2-5 )alkoxycarbonyl, (e.g. methoxycarbonyl, tert-butoxycarbonyl), benzyloxycarbonyl, halogenated lower (C 1-4 )alkanoyl (e.g. trifluoroacetyl, chloroacetyl), etc.
- lower (C 1-4 ) alkanoyl e.g. formyl, acetyl
- lower (C 2-5 )alkoxycarbonyl e.g. methoxycarbonyl, tert-butoxycarbonyl
- benzyloxycarbonyl e.g. trifluoroacetyl, chloroacetyl
- halogenated lower (C 1-4 )alkanoyl e.g. trifluoroacetyl, chloroacet
- Removal of such protective groups can be accomplished by methods known perse (e.g. reduction, acid decomposition, hydrolysis).
- the maytansinoid compound (I) produced in the described manner can be isolated and recovered from the reaction mixture by conventional procedures, e.g. concentration, solvent extraction, chromatography, recrystallization, etc.
- the maytansinoid compound (I) according to this invention has potent antimitotic activity and antitumor activity with comparatively low toxicity, and when administered to tumor-bearing animals [e.g. leukemia (P-388, mouse), melanoma (B-16, mouse)], inhibits the growth of tumor cells and produces a marked increase of survival time. Therefore, the compound (I) can be used as an effective antitumor drug for warm-blooded animals (e.g. mouse, rat, rabbit, dog, cat, man).
- the compound (I) is safely administered orally or parenterally as a suitable pharmaceutical composition (e.g. injection) as formulated with a per se known carrier, diluent or the like.
- the dosage may be decided from the range of about 1 to 500 ⁇ g/kg body weight per injection, preferably 5 to 100 I tg/kg body weight, with reference to the condition, animal species and other factors.
- An injection may be prepared in the established manner, for example by dissolving about 50 ⁇ g to 3 mg of compound (I) in about 0.5 ml of alcohol (e.g. ethanol) and making it up to 10 ml with physiological saline. When a small dosage is indicated, the above solution may be further diluted with physiological saline.
- alcohol e.g. ethanol
- the maytansinoid compound (I) of this invention is useful in that it displays antimicrobial activity, e.g. antifungal and antiprotozoal activities.
- the maytansinoid compounds (I) are useful for treating Tetrahymena pyriformis W.
- compound (I) can be advantageously used for the investigation of bacterial flora in soils, active sludge, animal body fluids, etc.
- test sample is added to a liquid or solid medium and 0.1 ml of a 1% methanol-water solution of about 10 to 100 pg/ml of compound (I) is added to the medium, followed by incubation.
- the starting compound (11) used for the production of the contemplated compound of this invention can be produced for example in accordance with the description in the specification of European Patent Publication No. 4466), i.e. by contacting a maytansinoid compound of the formula: wherein X and R 1 are as previously defined, with a culture broth, inclusive of processed matters derived therefrom, of a microorganism belonging to the genus Bacillus, the genus Streptomyces or the genus Actinomyces which is capable of transforming the 20-methoxy group of (IV) into a hydroxyl group.
- the microorganisms thus useful for the method of transforming the 20-methoxy group into a hydroxyl group include strains of the genera Bacillus, Streptomyces and Actinomyces, and their mutants, which are capable of transforming the methoxy group in 20-position of maytansinoid compound (IV) into a hydroxyl group.
- the microorganisms useful for the purpose are Bacillus megaterium IFO 12108, Streptomyces flavotricini IFO 12770, Streptomyces platensis IFO 12901, Streptomyces libani IFO 13452 and Actinomyces nigrescens IFO 12894.
- the microorganisms given IFO numbers above have been listed on the List of Cultures, 1978 (Sixth Edition), published by Institute for Fermentation, Osaka. The microorganisms listed there are available from the same Institute.
- dechloromaytansinoid compound i.e. dechloromaytansinoid compound
- dechloromaytansinoid compound can be produced for example in accordance with the description in the specification of European Patent Publication No. 11277), i.e., by acylating dechloromaytansinol of the formula: with a carboxylic acid of the formula: wherein R 1 is as previously defined, or a reactive derivative thereof.
- the dechloromaytansinol (V) can be produced by reducing a compound (IV) in which X is CI with a metal hydride (e.g. lithium aluminum hydride).
- Rf values are those found on silical gel TLC (Merck, HPTLC) unless otherwise indicated.
- Ansamitocin P-2, P-3 and P-4 mean the compounds (IV) in which X is CI and R 1 means ethyl, isopropyl and isobutyl, respectively.
- PDM-3 is a compound (II) in which X is CI and R 1 is isopropyl, i.e. 20-demethoxy-20-hydroxymaytansinol 3-isobutyrate.
- Dechloro-PDM-3 means a compound (II) in which X is H and R 1 is isopropyl, i.e. 19-dechloro-20-demethoxy-20-hydroxymaytensinol 3-isobutyrate.
- anhydrous tetrahydrofuran THF
- Ansamitocin mixture 12% of Ansamitocin P-2, 71 % of P-3 and 17% of P-4
- the solution is cooled to -50°C in a dry ice-ethanol bath.
- 13.0 g of lithium aluminum hydride (LAH) is added at one stroke and the mixture is stirred at a temperature from -50°C to -22°C for 2 hours.
- a further 3 g of LAH is added and the reaction mixture is stirred at -28°C to -22°C for 80 minutes.
- fractions 35 to 52 are pooled, the solvent distilled off and the residue dried in vacuo to obtain 7.25 g of maytansinol. Then, fractions 53 to 68 are similarly treated to obtain 1.55 g of a substantially equimolar mixture of maytansinol and dechloromaytansinol. Similarly, fractions 69 to 86 yield 0.78 g of dechloromaytansinol.
- UV spectrum nm 231.5, 241.5, 250.5, 277.5, 286
- UV spectrum nm 232.5, 241, 251, 277.5, 285.5
- Streptomyces flavotricini IFO 12770 is used to inoculate a culture medium composed of 1% dextrin, 1 % glucose, 1 % glycerol, 0.5% peptone, 0.5% yeast extract, 0.5% meat extract, 0.3% NaCI and 0.5% calcium carbonate (pH 7.2), and is cultivated under shaking at 28°C for 48 hours. To a 2 I portion of this culture is added 20 mg of Ansamytocin P-3 and the reaction is conducted under shaking at 28°C for 48 hours. The reaction mixture is then extracted with ethyl acetate and the extract is filtered, washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried and concentrated under reduced pressure.
- dechloro-PDM-3 is obtained from dechloromaytansinol 3-isobutyrate.
- Example 1 101.2 mg of PDM-3 and 215.4 mg of p-chlorobenzenesulfonyl chloride are reacted in 2.0 ml of anhydrous pyridine at room temperature for 5 hours.
- Example 1 94.2 mg of PDM-3 and 218.7 mg of p-acetamidobenzenesulfonyl chloride are reacted in 2.2 ml of anhydrous pyridine at room temperature for 3 days.
- the pyridine is distilled off, the residue is dissolved in chloroform and the solution is washed and dried as in Example 1.
- PDM-3 (101.2 mg) and 289.5 mg of p-trifluoroacetamidobenzenesulfonyl chloride are stirred in 2 ml of anhydrous pyridine at room temperature for 4 hours.
- the reaction mixture is worked up as in Example 1 to obtain PDM-3-C 20 -p-trifluoroacetamidobenzenesulfonate as a crude product.
- dechloro-PDM-3-C 20 -methanesulfonate is obtained from 31.5 mg of dechloro-PDM-3, 50 ⁇ l of methanesulfonyl chloride and 1 ml of anhydrous pyridine.
- Example 1 As in Example 1, 95.8 mg of PDM-3 and 191 mg of a-toluenesulfonyl chloride (benzylsulfonyl chloride) are reacted in 2.0 ml of anhydrous pyridine at room temperature overnight. Then, the reaction mixture is worked up as in Example 1 and chromatographed on silica gel (SiO 2 , 30 g; solvent: ethyl acetate), the eluate being collected in 10-g fractions to yield 97.0 mg of PDM-3-C 20 - ⁇ -toluenesulfonate (PDM-3-C 20 -benzylsulfonate). Mass spectrum (m/e): 713(M + -61).
- a-toluenesulfonyl chloride a-toluenesulfonyl chloride
- PDM-3 (112.8 mg) is dissolved in 3 ml of dry pyridine. To this solution, 76 ⁇ l of ethanesulfonyl chloride is added dropwise with stirring and the mixture is stirred at room temperature for 3 hours. Then, 100 ⁇ l of ethanesulfonyl chloride is further added and the mixture is stirred at the same temperature for another 3 hours. Then, the pyridine is evaporated off under reduced pressure and the residue extracted with ethyl acetate. The extract is washed three times with aqueous NaCI solution and dried.
- Antiprotozoal activity of compound (I) was assayed with Tetrahymena pyriformis W as the test organism and a medium composed of 20 g tryptose-peptone (Difco Co.), 1 g yeast extract, 2 g glucose, 1000 ml distilled water, 10 ml 1 M phosphate buffer (pH 7.0) as the assay medium.
- the microorganism was incubated at 28°C for 44 to 48 hours and the growth inhibitory activity of compound (1) was assayed by the serial dilution method.
- the minimal inhibitory concentrations of compound (I) are shown in Table 2.
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- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
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- Biochemistry (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Public Health (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (14)
dadurch gekennzeichnet, daß eine Verbindung der Formel
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT80104462T ATE2432T1 (de) | 1979-07-31 | 1980-07-29 | Maytansinoide, ihre herstellung und sie enthaltende therapeutischen zusammensetzungen. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9801079A JPS5622790A (en) | 1979-07-31 | 1979-07-31 | Novel maytansinoid compound and its preparation |
JP98010/79 | 1979-07-31 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0025108A1 EP0025108A1 (de) | 1981-03-18 |
EP0025108B1 true EP0025108B1 (de) | 1983-02-09 |
Family
ID=14207775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP80104462A Expired EP0025108B1 (de) | 1979-07-31 | 1980-07-29 | Maytansinoide, ihre Herstellung und sie enthaltende therapeutischen Zusammensetzungen |
Country Status (6)
Country | Link |
---|---|
US (1) | US4264596A (de) |
EP (1) | EP0025108B1 (de) |
JP (1) | JPS5622790A (de) |
AT (1) | ATE2432T1 (de) |
CA (1) | CA1148489A (de) |
DE (1) | DE3061903D1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100849311B1 (ko) * | 2001-03-15 | 2008-07-29 | 바스프 에스이 | 5-페닐피리미딘, 그의 제조를 위한 방법 및 중간 생성물,및 병원성 진균을 방제하기 위한 그의 용도 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1982001188A1 (en) * | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US5208020A (en) * | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
IL121789A (en) * | 1996-10-03 | 2001-06-14 | Rohm & Haas | A medicinal product for inhibiting mammalian cell tumors |
US7589180B2 (en) | 2001-05-11 | 2009-09-15 | Abbott Laboratories Inc. | Specific binding proteins and uses thereof |
US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
US20110313230A1 (en) | 2001-05-11 | 2011-12-22 | Terrance Grant Johns | Specific binding proteins and uses thereof |
MX338185B (es) * | 2007-01-25 | 2016-04-05 | Dana Farber Cancer Inst Inc | Uso de anticuerpos anti-egfr en el tratamiento de enfermedad mediada por egfr mutante. |
WO2008115404A1 (en) * | 2007-03-15 | 2008-09-25 | Ludwing Institute For Cancer Research | Treatment method using egfr antibodies and src inhibitors and related formulations |
EP2188311B1 (de) | 2007-08-14 | 2016-10-05 | Ludwig Institute for Cancer Research Ltd. | Auf den egf-rezeptor zielender, monoklonaler antikörper 175 und derivate und anwendungen davon |
US20110076232A1 (en) * | 2009-09-29 | 2011-03-31 | Ludwig Institute For Cancer Research | Specific binding proteins and uses thereof |
EP3904358A1 (de) * | 2012-09-26 | 2021-11-03 | ImmunoGen, Inc. | Verbesserte verfahren zur acylierung von maytanisol |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3896111A (en) * | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4162940A (en) * | 1977-03-31 | 1979-07-31 | Takeda Chemical Industries, Ltd. | Method for producing Antibiotic C-15003 by culturing nocardia |
US4137230A (en) * | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
GR63147B (en) * | 1978-03-24 | 1979-09-24 | Takeda Chemical Industries Ltd | Preparation process of demethyl maytansinoids |
JPS5566586A (en) * | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55102583A (en) * | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
-
1979
- 1979-07-31 JP JP9801079A patent/JPS5622790A/ja active Pending
-
1980
- 1980-07-23 US US06/171,460 patent/US4264596A/en not_active Expired - Lifetime
- 1980-07-29 EP EP80104462A patent/EP0025108B1/de not_active Expired
- 1980-07-29 AT AT80104462T patent/ATE2432T1/de not_active IP Right Cessation
- 1980-07-29 DE DE8080104462T patent/DE3061903D1/de not_active Expired
- 1980-07-30 CA CA000357361A patent/CA1148489A/en not_active Expired
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100849311B1 (ko) * | 2001-03-15 | 2008-07-29 | 바스프 에스이 | 5-페닐피리미딘, 그의 제조를 위한 방법 및 중간 생성물,및 병원성 진균을 방제하기 위한 그의 용도 |
Also Published As
Publication number | Publication date |
---|---|
EP0025108A1 (de) | 1981-03-18 |
JPS5622790A (en) | 1981-03-03 |
US4264596A (en) | 1981-04-28 |
CA1148489A (en) | 1983-06-21 |
DE3061903D1 (en) | 1983-03-17 |
ATE2432T1 (de) | 1983-03-15 |
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